Technical Field
Therapeutics are needed for treating diseases and disorders related to aberrant calcium-activated chloride channel (CaCC) activity, such as cystic fibrosis dry mouth, dry eye, and gastrointestinal hypomotility disorders. Small molecule compounds are described herein that are potent activators of CaCC activity and may be used for treating such diseases and disorders.
Description of the Related Art
Lung disease pathogenesis in cystic fibrosis (CF) is thought to involve distinct defects in airway submucosal gland fluid secretion, causing secretion of hyperviscous mucus (Boucher (2007) Annu. Rev. Med. 58, 157-170), and in airway surface transport, causing reduced airway surface liquid volume (Verkman et al. (2003) Am. J. Physiol. Cell Physiol. 284, C2-15). Both related defects are likely attributed to defective cystic fibrosis transmembrane conductance regulator (CFTR)-mediated secretion, and perhaps epithelial sodium channel (ENaC) hyperactivity, though the evidence remains controversial (Donaldson et al. (2007) Chest. 132, 1631-1636). Small-molecule therapies under development to correct the underlying CFTR defect include correctors, potentiators, and read-though enhancers to restore Cl− conductance in cells expressing CF-causing mutant CFTRs (Verkman, A. S., and Galietta, L. J. (2009) Chloride channels as drug targets. Nat. Rev. Drug. Discov. 8, 153-171; Sloane, et al. (2010) Curr. Opin. Pulm. Med. 16, 591-597), as well as gene replacement therapies (White et al. (2006) Med. Chem. 2, 499-503. Therapies targeting the activation of alternative Cl− channels, the calcium-activated chloride channels (CaCCs), have received considerable attention as well, as CaCCs are robustly expressed in non-CF and CF airways where CFTR is normally expressed. Other disorders associated with Cl− channel dysfunction include salivary gland dysfunction, such as in Sjogren's syndrome and following radiation injury, dry eye syndrome, and intestinal hypomotility. Drug candidates for treatment of these diseases and disorders are needed (Verkman et al., (2009) Nat. Rev. Drug Discovery 8, 153-171; Tabbara et al. (2000) Curr Opin Ophthalmol 11, 449-454).